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J. Biol. Chem., Vol. 265, Issue 12, 6669-6674, Apr, 1990
P Savagner, T Miyashita and Y Yamada
Collagen II, the major component of cartilage, is synthesized primarily by
chondrocytes and by certain cells in the eye. Previously, we have studied
the regulatory regions of the collagen II gene by DNA transfection assays
(Horton, W., Miyashita, T., Kohno, K., and Yamada, Y. (1987) Proc. Natl.
Acad. Sci. U.S.A. 84, 8864-8868). These studies show that both the promoter
and an enhancer sequence in the first intron are required for high
transcriptional activity in chondrocytes. These elements do not show
significant activity in cells which do not synthesize collagen II, such as
in muscle cells and fibroblasts. In this report, we have constructed
plasmids containing various deletions of the promoter of the collagen II
gene, fused to a reporter gene for chloramphenicol acetyltransferase (CAT)
and transfected them into both chick embryonic fibroblasts and HeLa cells.
We have found that silencer elements in the collagen II promoter region
reduce CAT activity 11-fold in fibroblasts, while not affecting the
enhancer-mediated transcription in chondrocytes. Deletions in the promoter
showed that most of the silencing activity was localized in two sites,
between -360 and -460 base pairs and between -620 and -700 base pairs.
Furthermore, a fragment containing these two sequences in a thymidine
kinase promoter CAT construct reduced the activity of the promoter in an
orientation independent fashion. Sequence analysis revealed that the two
silencer regions are homologous and contain consensus motifs for silencer
elements found in other genes. Gel retardation experiments showed that
nuclear factors from HeLa cells bind specifically to a DNA fragment
containing the silencer, whereas chondrocyte nuclear extracts did not show
any activity. Thus, our study indicates that the expression of the collagen
II gene is controlled by both negative and positive elements to ensure that
the gene is only expressed in suitable cells.
Two silencers regulate the tissue-specific expression of the collagen II gene
Laboratory of Developmental Biology and Anomalies, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892.
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